A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing pathogen, such as a microorganism in weakened or killed forms or an antigen derived from the microorganism. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and “remember” it, so that the immune system can more easily recognize and destroy the pathogen that it later encounters. A successful immune response is characterized by, e.g., eradication of pathogens, tissue repair, and short and long term immune memory. Vaccines can be prophylactic (e.g., to prevent or ameliorate the effects of a future infection by a pathogen), or therapeutic (e.g., vaccines against cancer or passive immunization against established infections, e.g., rabies). A vaccine often contains, or is administered with, an adjuvant. A vaccine adjuvant is an agent that stimulates the immune system and increases the immune system's response to a vaccine. The adjuvant itself typically does not have any specific antigenicity.
Vaccination is the most effective public health measure to prevent infectious disease associated morbidity and mortality. Improving vaccines against bacterial pathogens like Mycobacterium tuberculosis or enteropathogenic bacteria like Shigella flexneri would significantly lower public health costs that result from treating these infections. Generally, there are two types of microbe-based vaccine—live vaccines, which contain live pathogens, and dead vaccines, which contain killed pathogens.
Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts (Brockstedt et al., Nat Med 11: 853-860 (2005); Cheers et al., Trends Microbiol 4: 453-455 (1996); Detmer et al., Microb Cell Fact 5: 23 (2006); Kawamura, et al., Infect. Immun. 62: 4396-4403 (1994); Lauvau, et al., Science 294: 1735-1739 (2001); von Koenig et al., Nature 297: 233-234 (1982)). This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts (Vance et al., Cell Host Microbe 6: 10-21 (2009)). However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen associated molecular patterns (PAMPs), which serve to alert the immune system (Medzhitov, Immunity 30: 766-775 (2009); Takeuchi et al., Cell 140: 805-820 (2010)) are present in both live and killed vaccines, suggesting that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity.
Attenuated live vaccines are often superior to dead vaccine preparations, but they still have the risk of causing a severe infection, especially in immunocompromised individuals. Attenuated vaccine strains are usually genetically engineered pathogens. There is a significant public concern about the release of such strains. In addition, there is a risk of spontaneous reversion to virulence in attenuated organisms. These risks not only limit the use of attenuated live vaccines, but also cause concern and impede compliance. Further, live vaccines are labile, requiring complicated measures for storing and shipping, and are more costly to handle than dead vaccines. Therefore, it would be advantageous to improve the efficacy of dead vaccines, to minimize the risks associated with immunization with live vaccines, as well as the costs of vaccine storage and handling. Such improvement would promote public health and lower health care costs.